The present invention relates to methods for the treatment of gastroparesis in males and females in particular treatment groups, such as diabetics. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
Gastroparesis, or delayed stomach emptying, is most often a complication of diabetes. Seven million people in the United States may be affected by diabetes, and up to 75% of diabetic patients may experience gastrointestinal dysfunction, including diabetic gastroparesis, a syndrome of delayed gastric emptying, leading to nausea, vomiting, abdominal pain and early satiety.
There is more than one cause of gastroparesis. Although diabetes is the most common known cause, gastroparesis can be the result of physical problems, medications, as well as metabolic, smooth muscle and nervous system disorders. For example, physical problems leading to gastroparesis can include scarring from tumors and ulcers, as well as surgery on the vagus nerve or stomach. Certain medications, including Cardizem and other calcium blockers, which slow contractions in the intestine or weaken the stomach, can contribute to gastroparesis. Hypothyroidism is an example of a metabolic disorder associated with gastroparesis. Smooth muscle disorders such as amyloidosis and scleroderma can cause gastroparesis, as can disorders of the nervous system, such as Parkinson""s disease and abdominal migraine, a syndrome characterized by recurrent sterotypic episodes of paroxysmal abdominal pain and nausea and/or vomiting.
In addition to symptoms such as nausea, vomiting, an early feeling of fullness when eating, weight loss, abdominal bloating and discomfort, gastroparesis can lead to several complications. For example, if food lingers too long in the stomach, it can cause problems like bacterial overgrowth from the fermentation of food. Also, the food can harden into solid masses called bezoars, that may cause nausea, vomiting, and obstruction in the stomach. Bezoars can be dangerous if they block the passage of food into the small intestine. In diabetic patients, gastroparesis can make diabetes worse by adding to the difficulty of controlling blood glucose. When food that has been delayed in the stomach finally enters the small intestine and is absorbed, blood glucose levels rise. Since gastroparesis makes stomach emptying unpredictable, a person""s blood glucose levels can be erratic and difficult to control. High blood glucose causes chemical changes in nerves and damages the blood vessels that carry oxygen and nutrients to the nerves. This can damage the vagus nerve, potentially leading to symptoms of gastroparesis, if blood glucose levels remain high over a long period of time.
Some of the treatments available to help manage gastroparesis include meal and food changes. A patient may be asked to eat six small meals a day, rather than three large ones. Several liquid meals a day may be recommended until the gastroparesis is corrected. Avoiding fatty and high-fiber foods may also be recommended, as fat naturally slows digestion and some high-fiber foods like oranges and broccoli contain material that cannot be digested. The indigestible part will remain in the stomach too long and possibly form bezoars.
If other approaches do not work, a patient may need surgery to insert a feeding tube. The tube is inserted through the skin on the abdomen into the small intestine. This allows nutrients to be put directly into the small intestine, bypassing the stomach altogether. A feeding tube can be temporary and is used only if necessary when gastroparesis is severe. As an alternative to a feeding tube, parenteral nutrition may be delivered. A catheter is inserted in a chest vein, leaving an opening outside the skin. For feeding, a bag containing liquid nutrients or medication is attached to the catheter, and fluid enters the bloodstream through the vein. This bypasses the digestive system when gastroparesis is severe and not helped by other methods.
In diabetic patients with gastroparesis, food is being absorbed more slowly and at unpredictable times. These patients may need to take insulin more often, take insulin after eating, rather than before, and check blood glucose levels frequently after eating, administering insulin whenever necessary.
These treatments clearly involve inconvenience to the patient, turning eating and mealtimes into challenges. In the cases of feeding tubes or catheters, surgical intervention may be associated with risks and complications that can accompany any surgery. What is needed is an intervention that is effective and less disruptive to the patient while lacking in significant side effects.
The present invention provides methods for the treatment of gastroparesis in males and females in particular treatment groups, including diabetics. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates. The compositions comprise quinolinones, including derivatives thereof. Quinolinones are also known as quinolones and oxo-quinolines.
It is not intended that the present invention be limited by the nature of the derivative. In one embodiment, the quinolinone derivative is cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril; 3,4-Dihydro-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2(1H)-quinolinone).
In yet other embodiments, metabolites of cilostazol are contemplated for use in the methods of the presently claimed invention. Metabolites of cilostazol include, but are not limited to monohydroxycilostazol, monohydroxydehydrocilostazol, 3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and dehydrocilostazol.
In another embodiment, the present invention contemplates halogenated quinolinones (e.g., fluoroquinolinone). In a preferred embodiment, the quinolinone is a thioquinolinone or a sulphinyl or suphonyl derivatives thereof. In one embodiment, the halogenated quinolinone is flosequinan [(xe2x88x92)-7-fluoro-1-methyl-3-(methyl-sulphinyl)-4(1H)-quinolinone]; [7-Fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolone]. In a preferred embodiment, an enantiomer of flosequinan is used.
In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of gastroparesis, and ii) a composition comprising a quinolinone selected from the group consisting of a racemic mixture of flosequinan and an enantiomer of flosequinan; and b) administering said composition to said male or female (e.g. such that said symptoms are reduced). It is not intended that the present invention be limited to particular symptoms of gastroparesis. A variety of such symptoms are contemplated, including but not limited to, nausea, early satiety, postprandial bloating and fullness, and vomiting. In one embodiment, the present invention contemplates administering said flosequinan to said male or female under conditions such that symptoms of said male or female are improved.
In another embodiment, the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of gastroparesis, and ii) cilostazol; and b) administering said cilostazol to said male or female (e.g. such that said symptoms are reduced). It is not intended that the present invention be limited to particular symptoms of gastroparesis. A variety of such symptoms are contemplated, including but not limited to, nausea, early satiety, postprandial bloating and fullness, and vomiting. In one embodiment, the present invention contemplates administering said cilostazol to said male or female under conditions such that symptoms of said male or female are improved.
It is not intended that the present invention be limited by the method of introduction of flosequinan or cilostazol. In one embodiment, the flosequinan or cilostazol are introduced into said male or female orally.
In a preferred embodiment, the male or female is an adult human and the oral dosage of flosequinan is in a single dose per day of up to approximately two hundred milligrams, and more preferably, between approximately twenty-five to approximately seventy-five milligrams. In another preferred embodiment, flosequinan is administered in a single oral dose per day of between approximately one hundred and twenty-five and approximately two hundred milligrams. In another preferred embodiment, the male or female is an adult human and the oral dosage of flosequinan is in three daily doses, before meals, each of up to approximately two hundred milligrams. In another embodiment, each of the three daily doses is between approximately twenty-five to approximately seventy-five milligrams. In another embodiment, flosequinan is administered in three oral doses per day, before meals, each dose being between approximately one hundred and twenty-five and approximately two hundred milligrams.
In another embodiment, the male or female is an adult human and the oral dosage comprises a purified enantiomer of flosequinan. In one embodiment, the oral dosage of a purified enantiomer of flosequinan is in a single dose per day of up to approximately two hundred milligrams, and more preferably between approximately fifty to approximately seventy-five milligrams. In another preferred embodiment, a purified enantiomer of flosequinan is administered in a single oral dose per day of between approximately twenty and approximately fifty, and even more preferably, between approximately ten and approximately twenty milligrams per day. In another embodiment, the male or female is an adult human and the oral dosage of a purified enantiomer of flosequinan is in three daily doses, before meals, each of up to approximately two hundred milligrams. In another embodiment, each of the three daily doses is between approximately one hundred and twenty-five to approximately two hundred milligrams, and in another embodiment, each of the three daily doses is between approximately fifty to approximately seventy-five milligrams, and in yet another embodiment, each of the three daily doses is between approximately twenty and approximately fifty milligrams. In another embodiment, each of the three daily doses is between approximately ten and approximately twenty milligrams.
In a preferred embodiment, the male or female is an adult human and the oral dosage of cilostazol is in a single dose per day of up to approximately two hundred milligrams, and more preferably, between approximately twenty-five to approximately one hundred milligrams. In an even more preferred embodiment, cilostazol is administered in two oral doses per day of between approximately fifty and approximately one hundred milligrams. In another preferred embodiment, the male or female is an adult human and the oral dosage of cilostazol is in three daily doses, before meals, each of up to approximately two hundred milligrams. In another embodiment, each of the three daily doses is between approximately twenty-five to approximately seventy-five milligrams, and in yet another embodiment, each of the three daily doses is between approximately fifty to approximately one hundred milligrams.
In other embodiments said flosequinan or cilostazol is introduced cutaneously, by standard injection or intranasally.
In one embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is free from cardiac disease; and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
In another embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is not being treated (and/or has not been treated in the past) with a drug that causes hypotensive effects, and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
In another embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is not being treated (and/or has not been treated in the past) with a nitrite or nitrate, and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
In one embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is free from cardiac disease, including, but not limited to, congestive heart failure; and ii) cilostazol; and b) introducing said cilostazol to said patient such that such symptoms are reduced.
In another embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is not being treated (and/or has not been treated in the past) with a drug that causes hypotensive effects, and ii) cilostazol; and b) introducing said cilostazol to said patient such that such symptoms are reduced.
In another embodiment, the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of gastroparesis who is not being treated (and/or has not been treated in the past) with a nitrite or nitrate, and ii) cilostazol; and b) introducing said cilostazol to said patient such that such symptoms are reduced.
The present invention also contemplates the use of a pharmaceutical composition to treat diabetic patients with symptoms of gastroparesis. For example, one embodiment comprises a) providing: i) a male or female subject with diabetes, and ii) flosequinan; and b) introducing said flosequinan to said subject with diabetes such that the condition of said subject is improved.
The present invention also contemplates the use of a pharmaceutical composition to treat diabetic patients with symptoms of gastroparesis. For example, one embodiment comprises a) providing: i) a male or female subject with diabetes, and ii) cilostazol; and b) introducing said cilostazol to said subject with diabetes such that the condition of said subject is improved.
It is not intended that the present invention be limited by the nature of the formulation. In one embodiment, the present invention contemplates a formulation comprising a quinolone or quinolinone or derivative thereof in a mixture comprising lactose.